Novel antifungal therapeutics

描述（由申请人提供）：拟议研究的意义和影响。有许多与血液感染的管理，特别是由A。烟曲霉和念珠菌属。从文献中可以清楚地看出，部分问题与缺乏不选择耐药菌株且无毒性或药物间相互作用的新药物疗法有关。关于我们的建议，有两点值得注意。首先，目前还没有新的抗真菌药物;新的药物是改造的三唑类或棘白菌素类，许多还没有进行临床评估。第二，尽管与AmpB相关的问题，包括毒性和AmpB的毒性较小的脂质体制剂的成本增加，这种药物仍然是氟康唑或棘白菌素在念珠菌血症的非血小板减少患者中的主要后备选择。在这方面，伏立康唑与氟康唑相比几乎没有优势。同样令人遗憾的理由也被用于治疗血小板减少症患者。我们研究的影响集中在初步数据上，这些数据表明，在几种念珠菌属、烟曲霉和C.新人类事实上，我们的化合物的最小杀真菌浓度（MFC）相当于最小抑制浓度（MIC）。这一点在药物研发中非常重要。最重要的是，我们的化合物对氟康唑和米卡芬净耐药念珠菌属和新型隐球菌具有抑制作用。这些新数据强烈表明，我们的化合物具有独特的靶标。此外，我们的目标发现方法现在集中在使用酵母敲除和过表达文库的遗传分析上。其他小组的原理验证研究为我们的实验提供了信心。问题是，抗真菌药物的选择很少，真菌疾病研究的领导者最近提出了开发新治疗方法的紧迫性。在具体目标3中，我们建议进行ADME/TOX研究以证明我们的化合物对人类细胞具有低毒性。

DESCRIPTION (provided by applicant): Significance and impact of proposed research. There are many associated with the management of blood stream infections caused especially by A. fumigatus and Candida species. It is clear from the literature that part of the problem is associated with the lack of new drug therapies that do not select for drug-resistant strains and that are free of toxicity or drug-drug interactions. There are two points of interest in regard to our proposal. First, there are no new classes of anti- fungals; the new drugs are remodeled triazoles or echinocandins, many still not evaluated clinically. Second, in spite of the problems associated with AmpB that include toxicity and increased cost of the less toxic liposomal preparations of AmpB, this drug remains as the major fall back choice to fluconazole or an echinocandin in the non-neutropenic patient with candidemia. In this regard, voriconazole offers little advantage over fluconazole. The same unfortunate rationale is used for treating patients that are neutropenic. The impact of our studies is focused upon preliminary data that indicate high susceptibilities to our compounds among several Candida species, Aspergillus fumigatus, and C. neoformans. In fact, the minimum fungicidal concentration (MFC) of our compounds is equivalent to the minimal inhibitory concentration (MIC). This feature is certainly important in drug discovery. Of utmost importance, our compounds are inhibitory to fluconazole- and micafungin-resistant Candida species and Cryptococcus neoformans. These new data strongly show that our compounds have a unique target(s). Furthermore, our approach to target discovery now focuses upon a genetic analysis using yeast knock-out and over expression libraries. Proof-of-principle studies by other groups provide confidence for our experiments. The point is that there are few choices among anti-fungal drugs, and urgency has been suggested recently by leaders in fungal disease research to develop new treatments. We propose in specific aim 3 that ADME/TOX studies be done to demonstrate that our compounds have low toxicity to human cells.